PROJECT SUMMARY Every year, over a million children who are HIV-exposed but uninfected (CHEU) are born in sub-Saharan Africa and this population will continue to increase with improving availability of antiretroviral therapy (ART). In utero HIV exposure has broad ranging health impacts and emerging data suggest that CHEU have higher risk of neurocognitive delay compared to unexposed children. But the contribution of biological factors, the psychosocial environment and maternal-child interactions to this delay remains poorly characterized. This proposal will take advantage of the unique opportunity to evaluate the impact of in utero HIV exposure on neurocognitive development in children in the context of an ongoing clinical study we are conducting in Malawi. We are screening pregnant women, enrolling infants and conducting immunological analysis of neonatal adaptive immunity in three categories: (1) CHEU born to women diagnosed with HIV at the first antenatal visit, thus exposed to uncontrolled viremia for at least half of gestation; (2) CHEU born to women initiated on ART prior to conception with undetectable viral loads; and (3) infants born to HIV uninfected mothers. We collect cord blood mononuclear cells at birth to conduct a detailed immunological analysis. In this proposal, we will increase our sample size, incorporate assessment of monocyte activation from cord blood specimens and extend follow up of these infants to five years of age. Our goal is to conduct rigorously validated longitudinal assessments of neurocognitive development and psychosocial factors including maternal mental health, socioeconomic status, HIV stigma, home environment and mother-child interactions. Our interdisciplinary study team of infectious disease specialists, developmental pediatricians, social scientists and immunologists will lead one of the first studies of CHEU in resource-limited settings to simultaneously address the impact of biological and psychosocial factors on neurocognitive development. We hypothesize that in utero exposure to HIV will impair neurocognitive development in the first five years of life and children born to HIV-infected mothers with untreated HIV infection at the start of pregnancy will demonstrate more delay than children of mothers with undetectable HIV viral load throughout pregnancy. We further hypothesize that both immunological status at birth and psychosocial factors will contribute to impaired neurocognitive development in CHEU. This study will provide detailed evidence to develop interventions to improve the well-being of CHEU in resource-limited settings.